The death receptors, belonging to the tumor necrosis factor receptor (TNFR) super family, are characterized by their cysteine rich domains in the extracellular region and death domains (DD) in the intracellular region. Death domain endows death receptor with function of inducing cell death by apoptosis, but sometime it also mediates other signals. Tumor necrosis factor-related apoptosis-inducing ligand, TRAIL (Wiley S R, Schooley K, Smolak P, et al., Identification and characterization of a new member of the TNF family that induces apoptosis, Immunity, 1995, 3:673-682) in combination with its death domains triggers two cell death signaling pathways, i.e., death receptor pathway and mitochondrion pathway, to kill various tumor cells, but is nontoxic to most normal human cells. Human T lymphocytes infected by HIV are more susceptible to TRAIL/TRAIL receptor-induced cytotoxicity than the normal T cells. These studies suggested attractive prospects of TRAIL and TRAIL receptor in the therapy of cancer and AIDS.
Five TRAIL receptors, i.e., DR4 (death receptor 4 or named as TRAIL-R1), DR5 (death receptor 5, or named as TRAIL-R2/TRICK2/KILLER), DcR1 (decoy receptor 1 or named as TRID/TRAIL-R3/LIT), DcR2 (TRAIL-R4 or named as TRUNDD), and osteoprotegerin (OPG), have been identified up to date. DR4 and DR5 possess functional intracellular death domain and can mediate apoptosis signals. DcR1 is anchored on the cell membrane via glycosyl phosphatidyl inositol (GPI) and contains no death domain at all, so that it cannot mediate cell death signals. DcR2 has an incomplete death domain, which neither mediate cell death signals. DcR1 can inhibit TRAIL to bind with a death domain as a receptor. DcR2 having an incomplete death domain serves as decoy receptors to inhibit the killing activity of TRAIL by competing association with TRAIL. Osteoprotegerin is a secretive receptor for TRAIL and can bind with TRAIL and inhibits TRAIL functions.
It was showed in prior art that mAbs against DR4 or DR5 could kill tumor cells without toxicity to normal cells. However, since the extracellular domain of DR4 or DR5 comprises various epitopes, the relationship between the biological activity of mAbs and the relevant epitopes have not been defined by known technologies.